Gemcitabine, a synthetic pyrimidine nucleoside antineoplastic agent causes cellular arrest by inhibiting ribonucleotide reductase and DNA synthesis. It is used in the treatment of the various types of cancer such as non-small cell lung cancer (NSCLC) when given alone or together with cisplatin, pancreatic cancer, breast cancer, when given together with paclitaxel, in treatment of ovarian cancer when given together with carboplatin and in treatment of bladder cancer when given together with cisplatin. The existing parenteral gemcitabine hydrochloride injections are available either in the form of a sterile lyophilized powder or a concentrated solution. Neither of these forms can be directly administered to a patient, rather they require manipulation. It is extremely important that no microbial contamination occurs during this manipulation and the sterile nature of the product is preserved. Thus the procedure requires that the hospital staff follow recommended sterile technique. Deviation from recommended sterile technique poses a risk to the patient. Moreover, manual manipulation such as steps of reconstitution, dilution and incorporation into a sterile aqueous vehicle suitable for intravenous infusion can result in the wrong dose being administered or even in the error of infusing different drug in cases where the patient is prescribed combination chemotherapy with multiple drugs or other medication errors.
Gemcitabine preparations required for parenteral administration are currently available in the form of lyophilizates (Gemzar®), which must be reconstituted before administration to the patient. However, these freeze-dried preparations have considerable disadvantages. First of all, the process of preparing these lyophilisates is complicated and costly. Secondly, reconstitution requires additional working steps and undesirable risks of personnel involved. In particular, reconstitution of drug solutions from a dry substance can result in what has been called the ‘spray-back effect,’ which may result in further contamination and risk of personnel. As described above, other errors in handling can lead to serious problems such as deviation in the concentration of active substance, or microbial contamination. Further, it is reported (See Physician Desk Reference, Gemzar) that the maximum concentration for Gemzar® upon reconstitution, is 40 mg/mL. It is reported that at concentrations greater than 40 mg/mL may result in incomplete dissolution, and therefore should be avoided. Further, for Gemzar® like products which require reconstitution, normal safety precautions need to be observed when preparing and disposing of the infusion solution. Handling of such products needs to be carried out in a safety box. Use of protective coats and gloves is suggested. Particularly, the package insert states that if no safety box is available, the equipment should be supplemented with a mask and protective glasses. Further, the pack insert provides precaution that during the use of the concentrate product, there are chances that the preparation can come into contact with the eyes, which may cause serious irritation. Again, since there is a human intervention, there are chances that the solution can be spilled on the skin.
A study of prior art reveals that attempts have been made to solve the above described problems but none has led to a large volume infusion dosage form of gemcitabine wherein the dosage form is a stable solution of a gemcitabine or its pharmaceutically acceptable salt in an aqueous vehicle in a large volume infusion container. For example, United States Patent Application Number US20060089328 describes an injectable pharmaceutical composition comprising a solution of gemcitabine having a pH of about 3.5 to about 10 and a gemcitabine concentration of about 0.5 mg/ml to about 16 mg/ml. This patent application describes a solution of gemcitabine which is prepared by aseptic filtration having 2 ml filled aseptically into 2 ml perforable stopper vials. Anohter prior art, US20060154891, mentions the gemcitabine solutions to be ready-to-use and gemcitabine concentrates. However, it is to be noted that the “ready-to-use” solution is the one which is not reconstituted from a solid, such as a crystalline or an amorphous solid or a lyophilisate, immediately before it is administered to a patient. Thus, this prior art teaches a ready to use solution having an intervening step of dilution or mixing before administration.
It is important to note that the concentrate of the prior art, needs to be withdrawn and diluted with a vehicle suitable for infusion for suitable dose. Risks associated with such manipulation, for example, the appearance of particulates or crystalline drug in the perfusate remains a possibility. Further, for higher doses such as 1500 mg or above, more than one vials of prior art either having the preconcentrate or the lyophilized powder, may be required to achieve the dose as against the single ready to be infused solution of the present invention which can be immediately given to the patients, with accurate dose. The present invention thus enables the user to avoid steps of using more than one vial, a small volume parenteral container, to arrive at higher doses that are not equivalent in a single vial.
PCT publication Number WO2007037793 (herein after referred to as WO'793) teaches flexible containers having multiple chambers so that incompatible solutions in different compartments are isolated and the container allow selective sterile admixing to form a ready-to-infuse formulation prior to administration. Thus, a stable ready-to-infuse solution is absent in any of the chambers, rather a solution which may be unstable over time is formed before administration and administered immediately.
A particular problem encountered with a large volume gemcitabine solution is disclosed in Xu et al (J. Am. Pharm. Assoc., Vol 39, No 4, July/August 1999, page no 509-513). The authors found that when lyophilized gemcitabine (Gemzar®—Eli Lilly and Company) was reconstituted with aqueous vehicles and the infusion solution was stored at 4° C. for 14 days or more, crystals of gemcitabine appeared. These crystals did not dissolve upon warming to room temperature. Thus, the prior large volume infusion solution formed on reconstitution was unstable. The present inventors were confounded with the same problem and infusion solutions of gemcitabine showed appearance of crystals or particulates when they were stored at 2-8° C. or at room temperatures. The present inventors have now surprisingly found large volume infusion dosage form of gemcitabine wherein the dosage form is a “stable solution” of gemcitabine or its pharmaceutically acceptable salt in an aqueous vehicle in a large volume infusion container and wherein the solution is ready-to-infuse. The large volume infusion dosage form of the present invention is “stable” and “ready to be infused” gemcitabine large volume solution meaning thereby that the solution is stable over time, is sterile, has a volume in excess of 100 ml and can be directly infused intravenously without any intervening step of reconstitution or dilution or mixing.
Thus, the present invention can be said to solve the unmet need of ready to be infused solution dosage form of gemcitabine, which is a large volume infusion dosage form of gemcitabine wherein the dosage form is a solution of a gemcitabine or its pharmaceutically acceptable salt in an aqueous vehicle in a large volume infusion container and wherein the solution is ready-to-be infused. The present inventors surprisingly found that a large volume infusion solution in a large volume infusion container was stable after it was subjected to terminal sterilization. The gemcitabine solution of the invention is stable for extended periods of time in the liquid state, without having to undergo a step of freeze-drying or reconstitution. That is it represents a substantial advancement over the art, and a major convenience to potential patients. The ready to infuse solution avoids the inconvenience of diluting a concentrated small volume gemcitabine hydrochloride parenteral formulation into infusion diluents prior to infusion, as well as eliminates the risk of microbiological contamination during aseptic handling and any potential calculation or dilution error.